Tan Kin Fai, Chia Le Yi, Maki Marwan Abdelmahmoud Abdelkarim, Cheah Shiau-Chuen, In Lionel Lian Aun, Kumar Palanirajan Vijayaraj
Department of Pharmaceutical Technology, Faculty of Pharmaceutical Sciences, UCSI University, No. 1, Jalan Menara Gading, Taman Connaught, Cheras, Kuala Lumpur, 56000, Malaysia.
Faculty of Medicine and Health Sciences, UCSI University, Bandar Springhill, Port Dickson, Negeri Sembilan, 71010, Malaysia.
Naunyn Schmiedebergs Arch Pharmacol. 2025 Jan 29. doi: 10.1007/s00210-025-03839-z.
The third most prevalent type of cancer in the world, colorectal cancer, poses a significant treatment challenge due to the nonspecific distribution, low efficacy, and high systemic toxicity associated with chemotherapy. To overcome these limitations, a targeted drug delivery system with a high cytotoxicity against cancer cells while maintaining a minimal systemic side effects represents a promising therapeutic approach. Therefore, the aim of this study was to develop an efficient gold nanocarrier for the targeted delivery of the anticancer agent everolimus to Caco-2 cells. A novel gold nanocomposite (EV-β-CD-HA-Chi-AuNCs) functionalized with a targeting ligand (hyaluronic acid), a permeation enhancement excipient (chitosan), and an anticancer inclusive compound consisting of beta-cyclodextrin and everolimus was proposed and prepared via Turkevich method. Characterization was performed with a UV spectrometer, FTIR, Zetasizer, and HRTEM. Its drug release profile was also evaluated in media with three different pH values. Cytotoxicity and biocompatibility studies were performed on a colorectal cancer cell line (Caco-2) and a normal fibroblast line (MRC-5), respectively, via xCELLigence real-time cellular analysis (RTCA) technology. The inhibitory effect on migration was also further tested via the xCELLigence RTCA technique and a scratch assay. Characterization studies revealed the successful formation of EV-β-CD-HA-Chi-AuNCs with a size and charge which are suitable for the use as targeted drug delivery carrier. In the cytotoxic study, the EV-β-CD-HA-Chi-AuNCs showed a lower IC (16 ± 1 µg/ml) than the pure drug (25 ± 3 µg/ml) toward a colorectal cell line (Caco-2). In the biocompatibility study, the EV-β-CD-HA-Chi-AuNCs have minimal toxicity, while the pure drug has severe toxicity toward healthy fibroblasts (MRC-5) despite its low concentration. In the cell migration study, the EV-β-CD-HA-Chi-AuNCs also showed a greater inhibitory effect than the pure drug. Compared with the pure drug, the EV-β-CD-HA-Chi-AuNCs exhibit an excellent selective cytotoxicity between cancerous colorectal Caco-2 cells and healthy MRC-5 cells, making it a potential carrier to carry the drug to the cancerous site while maintaining its low toxicity to the surrounding environment. In addition, an increase in the cytotoxic activity of the EV-β-CD-HA-Chi-AuNCs toward cancerous colorectal Caco-2 cells was also observed, which can potentially improve the treatment of colorectal cancer.
结直肠癌是全球第三大常见癌症类型，由于化疗存在非特异性分布、疗效低和全身毒性高的问题，给治疗带来了重大挑战。为克服这些局限性，一种对癌细胞具有高细胞毒性同时保持最小全身副作用的靶向药物递送系统是一种很有前景的治疗方法。因此，本研究的目的是开发一种高效的金纳米载体，用于将抗癌药物依维莫司靶向递送至Caco-2细胞。通过Turkevich方法提出并制备了一种新型金纳米复合材料（EV-β-CD-HA-Chi-AuNCs），其用靶向配体（透明质酸）、渗透增强赋形剂（壳聚糖）以及由β-环糊精和依维莫司组成的抗癌包合物进行了功能化。用紫外光谱仪、傅里叶变换红外光谱仪、Zetasizer和高分辨透射电子显微镜进行了表征。还在三种不同pH值的介质中评估了其药物释放曲线。分别通过xCELLigence实时细胞分析（RTCA）技术对结肠癌细胞系（Caco-2）和正常成纤维细胞系（MRC-5）进行了细胞毒性和生物相容性研究。还通过xCELLigence RTCA技术和划痕试验进一步测试了对迁移的抑制作用。表征研究表明成功形成了EV-β-CD-HA-Chi-AuNCs，其大小和电荷适合用作靶向药物递送载体。在细胞毒性研究中，EV-β-CD-HA-Chi-AuNCs对结肠癌细胞系（Caco-2）的半数抑制浓度（IC）（16±1μg/ml）低于纯药物（25±3μg/ml）。在生物相容性研究中，EV-β-CD-HA-Chi-AuNCs毒性极小，而纯药物尽管浓度低，但对健康成纤维细胞（MRC-5）具有严重毒性。在细胞迁移研究中，EV-β-CD-HA-Chi-AuNCs也显示出比纯药物更强的抑制作用。与纯药物相比，EV-β-CD-HA-Chi-AuNCs在结肠癌细胞Caco-2和健康细胞MRC-5之间表现出优异的选择性细胞毒性，使其成为一种潜在的载体，可将药物携带至癌组织部位，同时对周围环境保持低毒性。此外，还观察到EV-β-CD-HA-Chi-AuNCs对结肠癌细胞Caco-2的细胞毒性活性增加，这可能会改善结直肠癌的治疗效果。
